We have completed the molecular biologic groundwork necessary to begin a large-scale synthetic effort to optimize our initial leads for in vivo use. Having now expressed both recombinant cysteine protease targets, we will screen compounds received from collaborating laboratories against Onchocerca, Brugia and mammalian homologues. Those which have specific efficacy against our parasite protease targets will be identified by direct enzyme screening. Both peptide and non-peptide derivatives will be assayed. Many of these compounds have already gone through preliminary toxicology and pharmacokinetic testing. Radiolabeled compounds will be synthesized to follow half-life and mode of clearance in vivo. Synthetic efforts will be aimed at maximizing efficacy and oral bioavailability, as has been successfully done for the antihypertensive protease inhibitor captopril, and protease inhibitors currently in clinical trials for HIV. Finally, we have successfully produced a computer graphics model of the active program for inclusion in our screening efforts and ultimate synthetic analoguing.